U.S. patent application number 16/778526 was filed with the patent office on 2020-12-31 for monolithic intravaginal rings comprising progesterone and methods of making and uses thereof.
This patent application is currently assigned to Ferring B.V.. The applicant listed for this patent is Ferring B.V.. Invention is credited to Salah U. Ahmed, Diane D. HARRISON, Anu MAHASHABDE, Jiaxiang TSAO.
Application Number | 20200405732 16/778526 |
Document ID | / |
Family ID | 1000005078730 |
Filed Date | 2020-12-31 |
United States Patent
Application |
20200405732 |
Kind Code |
A1 |
Ahmed; Salah U. ; et
al. |
December 31, 2020 |
MONOLITHIC INTRAVAGINAL RINGS COMPRISING PROGESTERONE AND METHODS
OF MAKING AND USES THEREOF
Abstract
The present invention relates to monolithic intravaginal rings
comprising progesterone, methods of making, and uses thereof. The
intravaginal rings comprise progesterone, a polysiloxane elastomer,
and a pharmaceutically acceptable hydrocarbon or glycerol esters of
a fatty acid.
Inventors: |
Ahmed; Salah U.; (New City,
NY) ; TSAO; Jiaxiang; (Nauet, NY) ;
MAHASHABDE; Anu; (Kendall Park, NJ) ; HARRISON; Diane
D.; (Villanova, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ferring B.V. |
Hoofddorp |
|
NL |
|
|
Assignee: |
Ferring B.V.
Hoofddorp
NL
|
Family ID: |
1000005078730 |
Appl. No.: |
16/778526 |
Filed: |
January 31, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14045311 |
Oct 3, 2013 |
10548904 |
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16778526 |
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12364990 |
Feb 3, 2009 |
8580293 |
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14045311 |
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61026115 |
Feb 4, 2008 |
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61139454 |
Dec 19, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B29K 2083/00 20130101;
A61K 9/0036 20130101; A61K 31/57 20130101; B29C 45/0001 20130101;
A61F 6/08 20130101; B29K 2105/0035 20130101; B29C 45/7207 20130101;
A61K 47/44 20130101; B29L 2031/753 20130101; A61K 47/34
20130101 |
International
Class: |
A61K 31/57 20060101
A61K031/57; A61F 6/08 20060101 A61F006/08; A61K 9/00 20060101
A61K009/00; A61K 47/34 20060101 A61K047/34; A61K 47/44 20060101
A61K047/44; B29C 45/00 20060101 B29C045/00; B29C 45/72 20060101
B29C045/72 |
Claims
1-52. (canceled)
53. A method of manufacturing a monolithic intravaginal
progesterone ring, comprising: (a) mixing progesterone, a
polysiloxane elastomer composition, and a pharmaceutically
acceptable hydrocarbon or glycerol esters of a fatty acid or
pharmaceutically acceptable oil, to form a homogeneous mixture; (b)
placing the homogeneous mixture into a mold; and (c) curing the
homogeneous mixture in the mold to form a monolithic intravaginal
progesterone ring comprising about 10% to about 30% by weight of
the progesterone, about 60% to about 80% by weight of polysiloxane
elastomer, and about 1% to about 8% by weight of the
pharmaceutically acceptable hydrocarbon or glycerol esters of fatty
acid or pharmaceutically acceptable oil, wherein the progesterone
is homogeneously dispersed in the elastomer.
54. The method of claim 53, wherein the polysiloxane elastomer is a
diorganopolysiloxane elastomer.
55. The method of claim 54, wherein the diorganopolysiloxane
elastomer is a dimethylpolysiloxane elastomer.
56. The method of claim 55, wherein the dimethylpolysiloxane
elastomer is vinyl end blocked.
57. The method of claim 55, wherein the dimethylpolysiloxane
elastomer further comprises a dimethylmethylhydrogen polysiloxane
crosslink.
58. The method of claim 53, wherein the polysiloxane elastomer
composition comprises, as separate components, (i)
dimethylpolysiloxane vinyl end-blocked polymer, non-crystalline
trimethylsilyl treated fumed silica, and a platinum silicone
complex and (ii) dimethylpolysiloxane vinyl end-blocked polymer,
non-crystalline trimethylsilyl treated fumed silica,
dimethylmethylhydrogen polysiloxane, and 2-methyl-3-butyn-2-ol.
59. The method of claim 58, wherein step (a) comprises: (a1) mixing
a first portion of the progesterone, the polysiloxane elastomer
composition component (i), and a first portion of the
pharmaceutically acceptable hydrocarbon or glycerol esters of fatty
acid or pharmaceutically acceptable oil, to form a first homogenous
mixture; (a2) mixing a second portion of the progesterone, the
polysiloxane elastomer composition component (ii), and a second
portion of the pharmaceutically acceptable hydrocarbon or glycerol
esters of fatty acid or pharmaceutically acceptable oil, to form a
second homogenous mixture; and (a3) mixing the first homogenous
mixture with the second homogenous mixture.
60. The method of claim 53, wherein the pharmaceutically acceptable
hydrocarbon or glycerol esters of fatty acid or pharmaceutically
acceptable oil is selected from mineral oil, silicone oil, and
combinations thereof.
61. The method of claim 53, wherein the pharmaceutically acceptable
hydrocarbon or glycerol esters of fatty acid or pharmaceutically
acceptable oil is mineral oil.
62. The method of claim 53, wherein the polysiloxane elastomer is a
dimethylpolysiloxane elastomer, and wherein the ratio of
progesterone to dimethylpolysiloxane elastomer to pharmaceutically
acceptable hydrocarbon or glycerol esters of fatty acid in the ring
is about 4:15:1.
63. The method of claim 53, wherein step (b) comprises injecting
the homogeneous mixture into the mold.
64. The method of claim 53, wherein step (c) comprises curing at a
temperature of from about 60.degree. C. to about 180.degree. C.
65. The method of claim 53, wherein step (c) comprises curing at a
temperature of from about 70.degree. C. to about 150.degree. C.
66. The method of claim 53, wherein step (c) comprises curing at a
temperature of from about 80.degree. C. to about 120.degree. C.
67. The method of claim 53, wherein the intravaginal ring
comprises: (a) from about 15% to about 25% by weight of the
progesterone; (b) from about 70% to about 80% by weight of a
dimethylpolysiloxane elastomer; and (c) from about 1% to about 8%
by weight of the pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid or pharmaceutically acceptable
oil.
68. A monolithic intravaginal ring for treating a luteal phase
defect in a patient in need thereof, comprising: (a) about 15% to
about 30% by weight of progesterone; (b) about 55% to about 90% by
weight of polysiloxane elastomer; and (c) about 1% to about 10% by
weight of a pharmaceutically acceptable hydrocarbon or glycerol
esters of a fatty acid or pharmaceutically acceptable oil, wherein
the progesterone is homogeneously dispersed in the elastomer.
Description
[0001] This application claims benefit of the filing dates of U.S.
Appl. No. 61/026,115, filed Feb. 4, 2008, and U.S. Appl. No.
61/139,454, filed Dec. 19, 2008, each of which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to monolithic intravaginal
rings comprising progesterone, methods of making, and uses thereof.
The intravaginal rings comprise progesterone, a polysiloxane
elastomer, and a pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid.
BACKGROUND OF THE INVENTION
[0003] Progesterone is a C-21 steroid hormone and belongs to a
class of hormones called progestogens. It is the major naturally
occurring steroid and is a precursor in the biosynthesis of other
steroids, particularly glucocorticoids, androgens and
estrogens.
[0004] Progesterone stimulates the growth of the uterus and also
stimulates a number of specific changes in the endometrium and
myometrium. Progesterone is essential for the development of
decidual tissue and the differentiation of luminal and glandular
epithelial tissue. It also plays several roles in gestation,
including breast enlargement, inhibition of uterine contractility,
maintenance of gestation, immunological protection of the embryo,
and inhibition of prostaglandin synthesis.
[0005] Progesterone has been used in the treatment of a number of
clinical disorders such as luteal phase defects, dysfunctional
uterine bleeding, endometriosis, endometrial carcinoma, benign
breast disease, pre-eclampsia, and regimens of in vitro
fertilization. The luteal phase of a natural cycle is characterized
by the formation of a corpus luteum, which secretes steroid
hormones, including progesterone. After fertilization and
implantation, the developing blastocyst secretes human chorionic
gonadotropin ("hCG"), which maintains the corpus luteum and its
secretions. Normal luteal function is essential for maintaining
pregnancy and data suggest that progesterone is necessary for the
maintenance of early pregnancy. Penzias, A. S., Fertility and
Sterility 77:318-323 (2002).
[0006] Unfortunately, not all women of reproductive age are able to
become pregnant, or maintain a pregnancy; indeed, about twelve to
fifteen percent of women of reproductive age in the United States
have received an infertility service at some time in their lives.
Assisted Reproductive Technology ("ART") generally involves the
surgical removal of eggs from a woman's ovaries, fertilizing them
with sperm in the laboratory, and then returning them to either the
donor woman's or another woman's uterus (Centers for Disease
Control, Assisted Reproductive Technology Success Rates, National
Summary and Fertility Clinic Reports. U.S. Department of Health and
Human Services, 2004). There are three types of ART: (a) IVF (in
vitro fertilization) involves extracting the eggs, fertilizing them
in the laboratory, and transferring resulting embryos to the uterus
through the cervix, (b) GIFT (gamete intrafallopian transfer)
involves placing unfertilized eggs and sperm into the woman's
fallopian tubes using a laparoscope through an abdominal incision,
and (c) ZIFT (zygote intrafallopian transfer) involves extracting
the eggs, fertilizing them in the laboratory, and using a
laparoscope to place the fertilized egg(s) into a woman's fallopian
tubes.
[0007] ART is also further classified by whether a woman's own eggs
were used (nondonor), or eggs were donated from another woman
(donor). In addition, the embryos used can be newly fertilized
(fresh), or previously fertilized, frozen, and then thawed
(frozen). For many women, in conjunction with ART, steps must be
taken to prime the uterus for implantation, and to sustain the
pregnancy after implantation. There have been many tools developed
to aid in this process.
[0008] In the mid-1980s, gonadotrophin releasing hormone ("GnRH")
agonists were incorporated into ovarian stimulation regimens and
are associated with improved outcomes after IVF and other assisted
reproductive technologies. GnRH agonists work by suppressing the
pituitary and preventing premature surges of endogenous luteinizing
hormone ("LH") during IVF cycles, allowing time for a larger number
of oocytes to reach maturity prior to harvesting as well as
increasing follicular growth. However, GnRH agonists inhibit the
corpora lutea in these cycles and may create an iatrogenic luteal
phase defect.
[0009] Use of a GnRH agonist causes suppression of pituitary LH
secretion for as long as 10 days after the last dose and pituitary
function may not return completely until 2-3 weeks after the end of
therapy. Without this LH signal, the corpus luteum may be
dysfunctional, and subsequent progesterone and estrogen secretion
may be abnormal, compromising endometrial receptivity, and
potentially leading to decreased implantation and pregnancy rates.
Pritts et al., Human Reproduction 17:2287-2299 (2002).
[0010] Various hormones, including estrogens, progesterone, and
hCG, have been used during the luteal phase and beyond in IVF
cycles for luteal phase support. A 1994 meta-analysis showed that
the use of hCG or progesterone led to significantly higher
pregnancy rates than placebo. Soliman et al., Fertility and
Sterility 61:1068-76 (1994). Progesterone in numerous forms (oral,
vaginal, intramuscular ("IM")) is considered to be the agent of
choice because hCG is associated with a higher risk of ovarian
hyperstimulation syndrome ("OHSS"), a potentially life-threatening
condition associated with an increased risk of thromboembolism.
[0011] Most treatment protocols advocate the use of progesterone
throughout the first trimester of pregnancy, since corpus luteum
activity has been demonstrated up to week 10 of pregnancy, although
progesterone supplementation continuing beyond a positive serum
pregnancy test may not be needed. The goal of progesterone
supplementation is therefore to assist a corpus luteum that may
have become compromised during ovulation induction or oocyte
retrieval.
[0012] Oral, IM, and intravaginal progesterone preparations are
available. Oral formulations appear to be inferior for luteal
support. Serum progesterone levels are highest with IM
administration, but because of the uterine first pass effect with
IM administration, vaginal administration results in higher
endometrial progesterone levels. Bulletti et al., Human
Reproduction 12:1073-9 (1997).
[0013] IM progesterone (50-100 mg daily) is widely used, but
requires daily injections and is painful, uncomfortable, and
inconvenient for patients; some patients may even develop a sterile
abscess or an allergic response to the oil vehicle. Toner J. P.,
Human Reproduction 15 Supp. 1:166-71 (2000). Vaginal progesterone
gel (Crinone.RTM./Prochieve.RTM. 8%; Columbia Laboratories,
Livingston, N.J.) is less painful and easier to use than IM, but
also requires daily dosing, may be messy, and due to potential
leakage, may not provide a full dose with every application.
Crinone.RTM. is a bioadhesive vaginal gel containing micronized
progesterone in an emulsion system. The carrier vehicle is an oil
in water emulsion containing the water swellable, but insoluble,
polymer polycarbophil.
[0014] The use of a progesterone vaginal insert (Endometrin.RTM.) 3
times daily has recently been approved by the U.S. Food and Drug
Administration ("FDA") to support embryo implantation and early
pregnancy by supplementation of corpus luteal function as part of
an ART treatment program for infertile women. In addition, vaginal
use multiple times daily of micronized progesterone capsules has
been reported and is used clinically, but luteal phase
supplementation or replacement is not an FDA-approved indication
for this product.
[0015] There is also published information comparing a vaginal
progesterone ring to IM progesterone for use in both IVF and oocyte
donation. Zegers-Hochschild et al., Human Reproduction 15:2093-2097
(2000).
[0016] Intravaginal devices for delivering progesterone and/or
intravaginal devices comprising polysiloxane elastomers are
discussed in U.S. Pat. Nos. 3,545,439; 3,948,262; 4,012,496;
5,869,081; 6,103,256; 6,056,976; and 6,063,395.
BRIEF SUMMARY OF THE INVENTION
[0017] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) a therapeutically effective amount of
progesterone, (b) a polysiloxane elastomer, and (c) a
pharmaceutically acceptable hydrocarbon or glycerol esters of a
fatty acid, wherein the polysiloxane elastomer is present in a
concentration of about 55% to about 90% by total weight of the
ring.
[0018] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) a therapeutically effective amount of
progesterone, (b) a polysiloxane elastomer, and (c) a
pharmaceutically acceptable oil, wherein the polysiloxane elastomer
is present in a concentration of about 55% to about 90% by total
weight of the ring.
[0019] The present invention is directed to a monolithic
intravaginal ring for treating a luteal phase defect in a patient
in need thereof, the ring comprising (a) about 5% to about 40% by
weight of progesterone, (b) about 55% to about 90% by weight of
polysiloxane elastomer, and (c) about 0.1% to about 10% by weight
of a pharmaceutically acceptable hydrocarbon or glycerol esters of
a fatty acid, wherein the progesterone is homogeneously dispersed
in the elastomer.
[0020] The present invention is directed to a monolithic
intravaginal ring for treating a luteal phase defect in a patient
in need thereof, the ring comprising (a) about 5% to about 40% by
weight of progesterone, (b) about 55% to about 90% by weight of
polysiloxane elastomer, and (c) about 0.1% to about 10% by weight
of a pharmaceutically acceptable oil, wherein the progesterone is
homogeneously dispersed in the elastomer.
[0021] The present invention is directed to a process for making a
monolithic intravaginal ring, the process comprising (a) mixing
progesterone, a pharmaceutically acceptable hydrocarbon or glycerol
esters of a fatty acid, and a polysiloxane to form a homogeneous
mixture, (b) placing the homogeneous mixture into a mold, and (c)
curing the mold at about 60.degree. C. to about 180.degree. C.,
wherein the polysiloxane is present in a concentration of about 55%
to about 90% by total weight of the ring.
[0022] The present invention is directed to a process for making a
monolithic intravaginal ring, the process comprising (a) mixing
progesterone, a pharmaceutically acceptable oil, and a polysiloxane
to form a homogeneous mixture, and (b) placing the homogeneous
mixture into a mold, wherein the polysiloxane is present in a
concentration of about 55% to about 90% by total weight of the
ring.
[0023] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to a patient a monolithic intravaginal
ring comprising (a) progesterone, (b) a dimethylpolysiloxane
elastomer, and (c) a pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid, wherein the ratio of progesterone
to elastomer is about 1:1 to about 1:10, the progesterone is
homogeneously dispersed in the elastomer, the ratio of progesterone
to hydrocarbon or glycerol esters of a fatty acid is about 1:0.1 to
about 1:100, and wherein the progesterone is released from the
monolithic intravaginal ring for up to about 18 days after
administration to the patient.
[0024] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to a patient a monolithic intravaginal
ring comprising (a) progesterone, (b) a dimethylpolysiloxane
elastomer, and (c) a pharmaceutically acceptable oil, in a ratio of
about 4:15:1, respectively, wherein the progesterone is
homogeneously dispersed in the elastomer, and wherein the
progesterone is released from the monolithic intravaginal ring for
up to about 18 days after administration to the patient.
[0025] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) about 15% to about 25% by weight of
progesterone, (b) about 70% to about 80% by weight of a
dimethylpolysiloxane elastomer, and (c) about 1% to about 10% by
weight of a pharmaceutically acceptable hydrocarbon or glycerol
esters of a fatty acid, wherein the progesterone is homogeneously
dispersed in the elastomer, and wherein the progesterone is
released from the monolithic intravaginal ring for up to about 18
days after administration to the patient.
[0026] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) about 15% to about 25% by weight of
progesterone, (b) about 70% to about 80% by weight of a
dimethylpolysiloxane elastomer, and (c) about 1% to about 10% by
weight of a pharmaceutically acceptable oil, wherein the
progesterone is homogeneously dispersed in the elastomer, and
wherein the progesterone is released from the monolithic
intravaginal ring for up to about 18 days after administration to
the patient.
[0027] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) progesterone, (b) a dimethylpolysiloxane
elastomer, and (c) mineral oil, in a ratio of about 4:15:1,
respectively, wherein the progesterone is homogeneously dispersed
in the elastomer, and released from the intravaginal ring at about
15 mg/day to about 25 mg/day in vivo and wherein the intravaginal
ring is replaced after about every 7 days following administration
to the patient.
[0028] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) about 20% progesterone, (b) about 75% MED-4840,
and (c) about 5% mineral oil, wherein the progesterone is
homogeneously dispersed in the elastomer, and released from the
intravaginal ring at about 15 mg/day to about 25 mg/day in vivo and
wherein the intravaginal ring is replaced after about every 7 days
following administration to the patient.
[0029] In some embodiments, the progesterone is homogeneously
dispersed in the polysiloxane elastomer.
[0030] In some embodiments, the polysiloxane elastomer is a
diorganopolysiloxane elastomer. The diorganopolysiloxane elastomer
can be a dimethylpolysiloxane elastomer. The dimethylpolysiloxane
elastomer can further comprise a dimethylmethylhydrogen
polysiloxane crosslink.
[0031] In some embodiments, the pharmaceutically acceptable
hydrocarbon or glycerol esters of a fatty acid is present in a
concentration of about 0.1% to about 10% by total weight of the
ring.
[0032] In some embodiments, the pharmaceutically acceptable
hydrocarbon or glycerol esters of a fatty acid is selected from
mineral oil, silicone oil and combinations thereof. In some
embodiments, the pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid is mineral oil.
[0033] In some embodiments, the progesterone is present in a
concentration of about 15% to about 30% by total weight of the
ring.
[0034] In some embodiments, the progesterone is released at a
steady rate for about 1 day to about 14 days. In some embodiments,
the progesterone is released at a steady rate for about 1 day to
about 10 days. In some embodiments, the progesterone is released at
a steady rate for about 1 day to about 7 days.
[0035] In some embodiments, the progesterone is released from the
monolithic intravaginal ring at a steady rate for up to about 10
days after administration to the patient. In some embodiments, the
progesterone is released from the monolithic intravaginal ring at a
steady rate for up to about 14 days after administration to the
patient. In some embodiments, the progesterone is released from the
monolithic intravaginal ring at a steady rate for up to about 18
days after administration to the patient.
[0036] In some embodiments, the polysiloxane is vinyl end blocked.
In some embodiments, the polysiloxane is dimethylpolysiloxane.
[0037] In some embodiments, the process further comprises mixing a
second polysiloxane into the homogeneous mixture prior to placing
into the mold. In some embodiments, the second polysiloxane is a
crosslinker. In some embodiments, the crosslinker is
dimethylmethylhydrogen polysiloxane.
[0038] In some embodiments, the placing of the homogeneous mixture
is by injection.
[0039] In some embodiments, the progesterone is released from the
intravaginal ring at about 10 mg/day to about 40 mg/day in vivo. In
some embodiments, the progesterone is released from the
intravaginal ring at about 10 mg/day to about 30 mg/day in vivo. In
some embodiments, the progesterone is released from the
intravaginal ring at about 15 mg/day to about 25 mg/day in
vivo.
[0040] In some embodiments, the intravaginal ring is replaced after
about 14 days following administration to the patient. In some
embodiments, the intravaginal ring is replaced after about 7 days
following administration to the patient.
BRIEF DESCRIPTION OF THE FIGURES
[0041] FIG. 1 depicts a top-down view of a monolithic intravaginal
ring of the present invention.
[0042] FIG. 2 depicts a process flow chart representing a process
for preparing monolithic intravaginal rings of the present
invention.
[0043] FIG. 3 shows a comparison of the mean serum estradiol levels
in a patient following administration of a progesterone
intravaginal ring of the present invention or a progesterone
vaginal gel.
[0044] FIG. 4 shows a comparison of the mean serum progesterone
levels in a patient following administration of a progesterone
intravaginal ring of the present invention or a progesterone
vaginal gel.
[0045] FIG. 5 shows the in vitro dissolution data and profile of a
progesterone intravaginal ring of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The present invention relates to monolithic intravaginal
rings comprising progesterone, methods of making, and uses thereof.
The intravaginal rings comprise progesterone, a polysiloxane
elastomer, and a pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid.
[0047] Throughout the present disclosure, all expressions of
percentage, ratio, and the like are "by weight" unless otherwise
indicated. As used herein, "by weight" is synonymous with the term
"by mass," and indicates that a ratio or percentage defined herein
is done according to weight rather than volume, thickness, or some
other measure.
[0048] As used herein, the term "about," when used in conjunction
with a percentage or other numerical amount, means plus or minus
10% of that percentage or other numerical amount. For example, the
term "about 80%," would encompass 80% plus or minus 8%.
[0049] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) a therapeutically effective amount of
progesterone, (b) a polysiloxane elastomer, and (c) a
pharmaceutically acceptable hydrocarbon or glycerol esters of a
fatty acid.
[0050] The term "therapeutically effective amount" refers to an
amount of the pharmaceutical composition (i.e., progesterone) that
treats a condition, disorder, or disease in a subject. The precise
therapeutic dosage of progesterone necessary to be therapeutically
effective can vary between subjects (e.g., due to age, body weight,
sex, condition of the subject, the nature and severity of the
disorder or disease to be treated, and the like). Thus, the
therapeutically effective amount cannot always be specified in
advance, but can be determined by a caregiver, for example, by a
physician using dose titration. Appropriate dosage amounts can also
be determined by routine experimentation with animal models.
[0051] The terms "treat" and "treatment" refer to both therapeutic
treatment and prophylactic or preventative measures, wherein the
object is to prevent or slow down (lessen) an undesired
physiological condition, disorder or disease, or obtain beneficial
or desired clinical results. For purposes of this invention,
beneficial or desired clinical results include, but are not limited
to, alleviation of symptoms; diminishment of extent of condition,
disorder or disease; stabilized (i.e., not worsening) state of
condition, disorder or disease; delay in onset or slowing of
condition, disorder or disease progression; amelioration of the
condition, disorder or disease state, whether detectable or
undetectable; or enhancement or improvement of condition, disorder
or disease. Treatment includes eliciting a clinically significant
response, without excessive levels of side effects.
[0052] The term "luteal phase defect" refers to a disruption in the
normal female menstrual cycle. The defect occurs when the female
body does not produce enough of the hormone progesterone. This
results in a delay in the development of the lining of the uterus
(endometrium) during the luteal phase. The luteal phase is defined
as the time between ovulation and the start of the next menstrual
cycle. Luteal phase defects can result in the inability to sustain
a pregnancy, whereby the uterine lining begins to break down,
bringing on menstrual bleeding and causing miscarriage.
[0053] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) a therapeutically effective amount of
progesterone, (b) a polysiloxane elastomer, and (c) a
pharmaceutically acceptable hydrocarbon or glycerol esters of a
fatty acid, wherein the polysiloxane elastomer is present in a
concentration of about 55% to about 90% by total weight of the
ring.
[0054] The present invention is also directed to a method for
treating a luteal phase defect in a patient in need thereof, the
method comprising administering to the patient a monolithic
intravaginal ring comprising (a) a therapeutically effective amount
of progesterone, (b) a polysiloxane elastomer, and (c) a
pharmaceutically acceptable oil, wherein the polysiloxane elastomer
is present in a concentration of about 55% to about 90% by total
weight of the ring.
[0055] The monolithic intravaginal ring of the present invention
can be useful as part of an assisted reproductive technology (ART)
treatment for infertile women with progesterone deficiency. The
monolithic intravaginal ring of the present invention can be useful
for luteal phase supplementation or replacement, e.g., partial
luteal support for in vitro fertilization or complete luteal
support for oocyte donation. The monolithic intravaginal ring of
the present invention can also be useful for the treatment of
secondary amenorrhea.
[0056] The term "monolithic intravaginal ring" refers to a ring
that is a matrix ring, wherein the matrix ring does not comprise a
membrane or wall that encloses a reservoir.
[0057] The intravaginal ring provides for administration or
application of an active agent to the vaginal and/or urogenital
tract of a subject, including, e.g., the vagina, cervix, or uterus
of a female. In some embodiments, the intravaginal ring is annular
in shape. As used herein, "annular" refers to a shape of, relating
to, or forming a ring. Annular shapes suitable for use with the
present invention include a ring, an oval, an ellipse, a toroid,
and the like.
[0058] The intravaginal ring of the present invention can be
flexible. As used herein, "flexible" refers to the ability of a
solid or semi-solid to bend or withstand stress and strain without
being damaged or broken. For example, the intravaginal ring of the
present invention can be deformed or flexed, such as, for example,
using finger pressure (e.g., applying pressure from opposite
external sides of the device using the fingers), and upon removal
of the pressure, return to its original shape. The flexible
properties of the intravaginal ring of the present invention are
useful for enhancing user comfort, and also for ease of
administration to the vaginal tract and/or removal of the device
from the vaginal tract.
[0059] The intravaginal ring of the present invention can be any
size suitable for placement in a vaginal tract. In some
embodiments, the outside diameter of the ring is about 35 mm to
about 65 mm, about 40 mm to about 60 mm, or about 45 mm to about 55
mm. In some embodiments, the outside diameter of the ring is about
55 mm. As used herein, an "outside diameter" refers to any straight
line segment that passes through the center of the ring and whose
endpoints are on the outer perimeter of the ring, see, e.g., FIG.
1.
[0060] In some embodiments, the inside diameter of the ring is
about 25 mm to about 45 min, or about 30 mm to about 40 mm. In some
embodiments, the inside diameter of the ring is about 38 mm. As
used herein, an "inside diameter" refers to any straight line
segment that passes through the center of the ring and whose
endpoints are on the inner perimeter of the ring, see, e.g., FIG.
1.
[0061] In some embodiments, the cross-sectional diameter of the
ring is about 5 mm to about 15 mm, or about 7 min to about 10 mm.
In some embodiments, the cross-sectional diameter is about 8.5 mm.
As used herein, a "cross-sectional diameter" refers to any straight
line segment whose endpoints are on the inner and outer perimeter
of the ring, see, e.g., FIG. 1.
[0062] In some embodiments, the monolithic intravaginal ring of the
present invention comprises progesterone (pregn-4-ene-3,20-dione),
as illustrated in Formula I.
##STR00001##
[0063] In some embodiments, the progesterone can be micronized. As
used herein, "micronized" refers to particles of a composition that
have been reduced to micron size.
[0064] As used herein, the term "particle size" refers to particle
diameter. Particle size and particle size distribution can be
measured using, for example, a Hyac/Royco particle size analyzer, a
Malvern particle size analyzer, a Beckman Coulter laser diffraction
particle size analyzer, a Shimadzu laser diffraction particle size
analyzer, or any other particle size measurement apparatus or
technique known to persons of ordinary skill in the art. As used
herein, the term "particle diameter" relates to a volumetric
measurement based on an approximate spherical shape of a particle.
The present invention can also comprise semi-spherical,
ellipsoidal, or cylindrical particles without limitation. In
addition to encompassing progesterone particles of a given size,
the present invention is also directed to compositions wherein the
distribution of particle sizes of progesterone and excipients is
controlled. As used herein, a "distribution" refers to the number
or concentration (i.e., percentage) of particles having a certain
size, or range of sizes, within a given lot, batch, or dosage form
of the present invention.
[0065] Materials used in the intravaginal ring of the present
invention are suitable for placement in the vaginal tract, i.e.,
they are nontoxic and can further be non-absorbable in the subject.
In some embodiments, the materials are compatible with an active
agent. In some embodiments, the materials can be capable of being
suitably shaped for intravaginal administration.
[0066] In some embodiments, the intravaginal ring comprises a
polymer material that is an elastomer, e.g., a thermosetting
elastomer, including, e.g., a silicone co-polymer (thermosetting
type). For example, the intravaginal ring of the present invention
can be produced using silicone polymers which can include various
catalysts or cross-linking agents. Such silicone compounds,
catalysts and cross-linking agents are known in the art, see e.g.,
U.S. Pat. No. 4,888,074. A silicone composition can include any
organo-silicone compound capable of cross-linking, with or without
the presence of cross-linking agents.
[0067] As used herein, an "elastomer" refers to an amorphous
polymer network formed when a polymer or a mixture of polymers
undergo cross-linking. Each polymer is comprised of monomeric
units, which are linked together to form the polymer. The monomeric
units can comprise carbon, hydrogen, oxygen, silicon, halogen, or a
combination thereof.
[0068] In some embodiments, the intravaginal ring comprises a
polysiloxane. As used herein, a "polysiloxane" refers to any of
various compounds containing alternate silicon and oxygen atoms in
either a linear or cyclic arrangement usually with one or two
organic groups attached to each silicon atom. For example,
polysiloxanes include substituted polysiloxanes, and
diorganopolysiloxanes such as diarylpolysiloxanes and
dialkylpolysiloxanes; an example of the latter is
dimethylpolysiloxane, as illustrated in Formula II.
##STR00002##
[0069] Such dimethylpolysiloxane polymers can be thermoset to the
corresponding elastomer by vulcanization with peroxide curing
catalysts, e.g., benzoyl peroxide or di-p-chlorobenzoyl peroxide at
temperatures of about 200.degree. C. and requiring additional heat
after treatment as described in U.S. Pat. Nos. 2,541,137;
2,723,966; 2,863,846; 2,890,188; and 3,022,951.
[0070] An example of a two-component dimethylpolysiloxane
composition, which is platinum-catalyzed at room temperature or
under slightly elevated temperature and capable of cross-linking,
is MED-4840 (NuSil Technology LLC, Carpinteria, Calif.). In some
embodiments of the present invention, a monolithic intravaginal
ring can comprise progesterone, mineral oil and MED-4840 elastomer.
The MED-4840 elastomer is composed of two parts, part A and part B.
The chemical composition of MED-4840 part A comprises
dimethylpolysiloxane vinyl endblocked polymer, fumed silica
(non-crystalline) trimethylsilyl treated and a platinum silicone
complex. The chemical composition of MED-4840 part B comprises a
dimethylpolysiloxane vinyl endblocked polymer, fumed silica
(non-crystalline) trimethylsilyl treated, dimethylmethylhydrogen
polysiloxane and 2-methyl-3-butyn-2-ol. Form A and form B undergo
cross-linkage to form a dimethylpolysiloxane elastomer.
[0071] In some embodiments of the present invention, the
polysiloxane elastomer is a diorganopolysiloxane elastomer. In some
embodiments, the diorganopolysiloxane elastomer is
dimethylpolysiloxane elastomer. In some embodiments, the
dimethylpolysiloxane elastomer further comprises a
dimethylmethylhydrogen polysiloxane cross-link. In some embodiments
of the present invention, the polysiloxane elastomer is
MED-4840.
[0072] In some embodiments, the polysiloxane elastomer is present
in a concentration of about 55% to about 90% by total weight of the
ring. In some embodiments, the polysiloxane elastomer is present in
a concentration of about 60% to about 80% by total weight of the
ring, or about 65% to about 75% by total weight of the ring.
[0073] In some embodiments, the monolithic intravaginal ring
comprises a pharmaceutically-acceptable hydrocarbon or glycerol
esters of a fatty acid. The glycerol esters of a fatty acid can be
monoesters, diesters, triesters and mixtures thereof. The fatty
acid glycerol esters can be of a synthetic or natural origin. In
some embodiments, the monolithic intravaginal ring comprises a
pharmaceutically-acceptable oil. In some embodiments the oil can be
a vegetable oil or a mineral oil. In some embodiments, the oil can
be olive oil, peanut oil, lanoline, silicone oil, mineral oil,
glycerine fatty acids or combinations thereof.
[0074] In some embodiments, the pharmaceutically acceptable
hydrocarbon or glycerol esters of a fatty acid is present in a
concentration of about 0.1% to about 10% by total weight of the
ring. In some embodiments the pharmaceutically acceptable
hydrocarbon or glycerol esters of a fatty acid is present in a
concentration of about 1% to about 6% by total weight of the ring.
In some embodiments of the present invention, the pharmaceutically
acceptable hydrocarbon or glycerol esters of a fatty acid is
mineral oil.
[0075] In some embodiments, progesterone is substantially
homogeneously dispersed in the intravaginal ring. As used herein,
"homogeneous" refers to a composition, e.g., the intravaginal ring,
that has a substantially uniform distribution of ingredients
throughout (i.e., an intravaginal ring of the present invention
does not have a composition gradient, or a multi-laminate
structure).
[0076] In some embodiments, the progesterone is present in a
concentration of about 1% to about 60% by total weight of the ring,
in a concentration of about 10% to about 40% by total weight of the
ring, in a concentration of about 15% to about 30% by total weight
of the ring, or in a concentration of about 20% to about 25% by
total weight of the ring.
[0077] In some embodiments, the intravaginal rings of the present
invention release about 10 mg to about 50 mg of progesterone/day in
vitro, about 10 mg to about 40 mg of progesterone/day in vitro,
about 10 mg to about 30 mg of progesterone/day in vitro, or about
10 mg to about 20 mg of progesterone/day in vitro.
[0078] In some embodiments, the intravaginal rings release about 14
mg to about 28 mg of progesterone/day in vitro, about 16 mg to
about 25 mg of progesterone/day in vitro, or about 18 mg to about
22 mg of progesterone/day in vitro. In some embodiments, the
intravaginal ring releases about 16 mg of progesterone/day in
vitro. In some embodiments, the intravaginal ring releases about 19
mg of progesterone/day in vitro.
[0079] In some embodiments, the intravaginal rings release about 25
mg to about 50 mg of progesterone/day in vitro, about 25 mg to
about 40 mg of progesterone/day in vitro, about 30 mg to about 40
mg of progesterone/day in vitro, or about 32 mg to about 36 mg of
progesterone/day in vitro.
[0080] As used herein, the "rate of release" or "release rate"
refers to an amount or concentration of active agent that is
released from the intravaginal ring over a defined period of time.
The release rate can be measured in vitro by placing the ring into
an Orbital shaker at 50 rpm containing 250 mL of 0.008 M SDS at
37.degree. C. The active agent can be assayed by methods known in
the art, e.g., by HPLC.
[0081] The intravaginal rings of the present invention can release
about 10 mg to about 40 mg of progesterone/day in vivo, about 10 mg
to about 30 mg of progesterone/day in vivo, about 10 mg to about 25
mg of progesterone/day in vivo, about 12 mg to about 25 mg of
progesterone/day in vivo, about 15 mg to about 25 mg of
progesterone/day in vivo, about 16 mg to about 24 mg of
progesterone/day in vivo, about 17 mg to about 22 mg of
progesterone/day in vivo, or about 18 mg to about 22 mg of
progesterone/day in vivo.
[0082] In some embodiments, the progesterone is released from the
intravaginal ring at a steady rate for up to about 18 days after
administration to a patient, for up to about 14 days after
administration to a patient, for up to about 7 days after
administration to a patient, or for up to about 4 days after
administration to a patient.
[0083] In some embodiments, after the first day of administration
to a patient, the progesterone is released at a steady rate for up
to about 17 additional days, for up to about 13 additional days,
for up to about 6 additional days, or for up to about 3 additional
days after administration.
[0084] As used herein, a "steady rate" is a release rate that does
not vary by an amount greater than about 70% of the amount of
progesterone released in vivo per day, by an amount greater than
about 60% of the amount of progesterone released in vivo per day,
by an amount greater than about 50% of the amount of progesterone
released in vivo per day, by an amount greater than about 40% of
the amount of progesterone released in vivo per day, by an amount
greater than about 30% of the amount of progesterone released in
vivo per day, by an amount greater than about 20% of the amount of
progesterone released in vivo per day, by an amount greater than
about 10% of the amount of progesterone released in vivo per day,
or by an amount greater than about 5% of the amount of progesterone
released in vivo per day.
[0085] In some embodiments, the steady rate encompasses a release
rate in vivo of about 15 mg/day to about 25 mg/day, about 16 mg/day
to about 24 mg/day, about 17 mg/day to about 22 mg/day or about 18
mg/day to about 20 mg/day. In some embodiments, the steady rate
encompasses a release rate of about 12 mg/day to about 16 mg/day,
about 12 mg/day to about 15 mg/day, about 12 mg/day to about 14
mg/day, or about 12 mg/day to about 13 mg/day. In some embodiments,
the steady rate encompasses about 13 mg/day to about 18 mg/day,
about 13 mg/day to about 17 mg/day, about 13 mg/day to about 16
mg/day, about 13 mg/day to about 15 mg/day, or about 13 mg/day to
about 14 mg/day. In some embodiments, the steady rate encompasses
about 11 mg/day to about 15 mg/day, about 11 mg/day to about 14
mg/day, about 11 mg/day to about 13 mg/day, or about 11 mg/day to
about 12 mg/day.
[0086] In some embodiments, the serum levels of progesterone are
maintained over a relatively constant level. In some embodiments,
serum progesterone levels are maintained at about 1 ng/mL to about
10 ng/mL, about 2 ng/mL to about 8 ng/mL, about 2 ng/mL to about 7
ng/mL, about 2 ng/mL to about 6 ng/mL, about 3 ng/mL to about 6
ng/mL, about 4 ng/mL to about 6 ng/mL, or about 5 ng/mL to about 6
ng/mL.
[0087] In some embodiments, serum progesterone levels are
maintained at about 4 ng/mL to about 10 ng/mL, about 4 ng/mL to
about 9 ng/mL, about 5 ng/mL to about 8 ng/mL, or about 6 ng/mL to
about 8 ng/mL.
[0088] In some embodiments, progesterone serum levels are
maintained below about 7 ng/mL, below about 6 ng/mL, below about 5
ng/mL, below about 4 ng/mL, below about 3 ng/mL, below about 2
ng/mL, or below about 1 ng/mL.
[0089] In some embodiments, these progesterone serum levels are
maintained from about 1 day to about 18 days after administration
to a patient, from about 1 day to about 14 days after
administration to a patient, from about 1 day to about 10 days
after administration to a patient, from about 1 day to about 7 days
after administration to a patient, or from about 1 day to about 4
days after administration to a patient. In some embodiments, these
progesterone serum levels are maintained from about 2 days to about
18 days after administration to a patient, from about 2 days to
about 14 days after administration to a patient, from about 2 days
to about 7 days after administration to a patient, or from about 2
days to about 4 days after administration to a patient.
[0090] In some embodiments, the present invention is directed to a
monolithic intravaginal ring for treating a luteal phase defect in
a patient in need thereof, the ring comprising about 5% to about
40% by weight of progesterone, about 55% to about 90% by weight of
polysiloxane elastomer, and about 0.1% to about 10% by weight of a
pharmaceutically acceptable hydrocarbon or glycerol esters of a
fatty acid, wherein the progesterone is homogeneously dispersed in
the elastomer.
[0091] In some embodiments, the present invention is directed to a
monolithic intravaginal ring for treating a luteal phase defect in
a patient in need thereof, the ring comprising about 5% to about
40% by weight of progesterone, about 55% to about 90% by weight of
dimethylpolysiloxane elastomer, and about 0.1% to about 10% by
weight of mineral oil, wherein the progesterone is homogeneously
dispersed in the elastomer.
[0092] In some embodiments, the present invention is directed to a
monolithic intravaginal ring for treating a luteal phase defect in
a patient in need thereof, the ring comprising about 10% to about
30% by weight of progesterone, about 60% to about 80% by weight of
polysiloxane elastomer, and about 1% to about 8% by weight of a
pharmaceutically acceptable hydrocarbon or glycerol esters of a
fatty acid, wherein the progesterone is homogeneously dispersed in
the elastomer.
[0093] In some embodiments, the present invention is directed to a
monolithic intravaginal ring for treating a luteal phase defect in
a patient in need thereof, the ring comprising about 10% to about
30% by weight of progesterone, about 60% to about 80% by weight of
dimethylpolysiloxane elastomer, and about 1% to about 8% by weight
of a mineral oil, wherein the progesterone is homogeneously
dispersed in the elastomer.
[0094] In some embodiments, the present invention is directed to a
monolithic intravaginal ring for treating a luteal phase defect in
a patient in need thereof, the ring comprising about 20% to about
25% by weight of progesterone, about 65% to about 75% by weight of
polysiloxane elastomer, and about 1% to about 6% by weight of a
pharmaceutically acceptable hydrocarbon or glycerol esters of a
fatty acid, wherein the progesterone is homogeneously dispersed in
the elastomer.
[0095] In some embodiments, the present invention is directed to a
monolithic intravaginal ring for treating a luteal phase defect in
a patient in need thereof, the ring comprising about 20% to about
25% by weight of progesterone, about 65% to about 75% by weight of
dimethylpolysiloxane elastomer, and about 1% to about 6% by weight
of a mineral oil, wherein the progesterone is homogeneously
dispersed in the elastomer, and wherein the progesterone is
released from the monolithic intravaginal ring for about 18 days
after administration to the patient.
[0096] The invention is directed to a process for making a
monolithic intravaginal ring, the process comprising (a) mixing
progesterone, a pharmaceutically acceptable hydrocarbon or glycerol
esters of a fatty acid, and a polysiloxane to form a homogeneous
mixture, (b) placing the homogeneous mixture into a mold and, (c)
curing the homogeneous mixture in the mold to form a monolithic
intravaginal ring comprising a polysiloxane elastomer, the
progesterone, and the pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid. In some embodiments of the present
invention, the polysiloxane is vinyl end blocked.
[0097] In some embodiments, the mold is cured at about 60.degree.
C. to about 180.degree. C., about 70.degree. C. to about
150.degree. C., about 80.degree. C. to about 120.degree. C., or
about 85.degree. C. to about 95.degree. C. In some embodiments, the
ring is cured outside the mold. In some embodiments, the process
further comprises mixing a second polysiloxane into the homogeneous
mixture prior to placing it into the mold. In some embodiments, the
second polysiloxane is a cross-linker. In some embodiments, the
cross-linker is dimethylmethylhydrogen polysiloxane. In some
embodiments, the placing of the homogeneous mixture into the mold
is by injection.
[0098] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to a patient a monolithic intravaginal
ring comprising (a) progesterone, (b) a dimethylpolysiloxane
elastomer, and (c) a pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid, wherein the ratio of progesterone
to elastomer is about 1:1 to about 1:10, the progesterone is
homogeneously dispersed in the elastomer, the ratio of progesterone
to hydrocarbon or glycerol esters of a fatty acid is about 1:0.1 to
about 1:100, and wherein the progesterone is released from the
monolithic intravaginal ring for up to about 18 days after
administration to the patient.
[0099] In some embodiments, the ratio of progesterone to elastomer
is about 1:1 to about 1:10, about 1:1 to about 1:8, about 1:1 to
about 1:6, about 1:1 to about 1:4, or about 1:2 to about 1:5.
[0100] In some embodiments, the ratio of progesterone to
hydrocarbon or glycerol esters of a fatty acid is about 1:0.1 to
about 1:100, about 1:0.1 to about 1:50, about 1:0.1 to about 1:25,
about 1:0.1 to about 1:10, or about 1:0.1 to about 1:1.
[0101] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to a patient a monolithic intravaginal
ring comprising (a) progesterone, (b) a dimethylpolysiloxane
elastomer, and (c) a pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid, in a ratio of about 4:15:1,
respectively (by weight), wherein the progesterone is homogeneously
dispersed in the elastomer, and wherein the progesterone is
released from the monolithic intravaginal ring for up to about 18
days after administration to the patient.
[0102] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to a patient a monolithic intravaginal
ring comprising (a) progesterone, (b) a dimethylpolysiloxane
elastomer, and (c) a pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid, in a ratio of about 20:90:1,
respectively (by weight), wherein the progesterone is homogeneously
dispersed in the elastomer, and wherein the progesterone is
released from the monolithic intravaginal ring for up to about 18
days after administration to the patient.
[0103] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to a patient a monolithic intravaginal
ring comprising (a) progesterone, (b) a dimethylpolysiloxane
elastomer, and (c) a pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid, in a ratio of about 40:40:1,
respectively (by weight), wherein the progesterone is homogeneously
dispersed in the elastomer, and wherein the progesterone is
released from the monolithic intravaginal ring for up to about 18
days after administration to the patient.
[0104] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) about 10% to about 40% by weight of
progesterone, (b) about 55% to about 90% by weight of a
dimethylpolysiloxane elastomer, and (c) about 0.1% to about 10% by
weight of a pharmaceutically acceptable hydrocarbon or glycerol
esters of a fatty acid, wherein the progesterone is homogeneously
dispersed in the elastomer, and wherein the progesterone is
released from the monolithic intravaginal ring for up to about 18
days after administration to the patient.
[0105] The present invention is directed to a method for treating a
luteal phase defect in a patient in need thereof, the method
comprising administering to the patient a monolithic intravaginal
ring comprising (a) about 15% to about 25% by weight of
progesterone, (b) about 70% to about 80% by weight of a
dimethylpolysiloxane elastomer, and (c) about 1% to about 10% by
weight of a pharmaceutically acceptable hydrocarbon or glycerol
esters of a fatty acid, wherein the progesterone is homogeneously
dispersed in the elastomer, and wherein the progesterone is
released from the monolithic intravaginal ring for up to about 18
days after administration to the patient.
[0106] In some embodiments, the intravaginal ring is replaced with
a new ring after about 18 days following administration to the
patient, after about 14 days following administration to the
patient, after about 10 days following administration to the
patient, after about 7 days following administration to the
patient, after about 5 days following administration to the
patient, after about 4 days following administration to the
patient, after about 3 days following administration to the
patient, or after about 2 days following administration to the
patient. In accordance with the present invention, the intravaginal
ring is not maintained longer than about 20 days before it is
replaced with a new ring.
[0107] The intravaginal ring can be administered about one to seven
days before embryo transfer, about two to six days before embryo
transfer, about two to five days before embryo transfer, or about
three to four days before embryo transfer. The administration of
the intravaginal ring can be supplemented by other hormone
administration, for example oral administration of estradiol.
[0108] In some embodiments, progesterone is administered via the
intravaginal ring of the present invention for about 10 weeks, for
about 8 weeks, for about 6 weeks, for about 4 weeks, for about 2
weeks, or for about 1 week.
[0109] In some embodiments, the present invention is directed to a
method for treating a luteal phase defect in a patient in need
thereof, the method comprising administering to the patient a
monolithic intravaginal ring comprising (a) progesterone, (b)
MED-4840, and (c) a pharmaceutically acceptable hydrocarbon or
glycerol esters of a fatty acid, wherein the ratio of progesterone
to MED-4840 is about 1:1 to about 1:10, the progesterone is
homogeneously dispersed in the elastomer, the ratio of progesterone
to hydrocarbon or glycerol esters of a fatty acid is about 1:0.1 to
about 1:100, wherein the progesterone is released from the
intravaginal ring at about 15 mg/day to about 25 mg/day in vivo,
and wherein the intravaginal ring is replaced after about every 7
days following administration to the patient.
[0110] In some embodiments, the present invention is directed to a
method for treating a luteal phase defect in a patient in need
thereof, the method comprising administering to the patient a
monolithic intravaginal ring comprising (a) progesterone, (b) a
dimethylpolysiloxane elastomer, and (c) mineral oil, in a ratio of
about 4:15:1, respectively, wherein the progesterone is
homogeneously dispersed in the elastomer, and released from the
intravaginal ring at about 15 mg/day to about 25 mg/day in vivo,
and wherein the intravaginal ring is replaced after about every 7
days following administration to the patient.
[0111] In some embodiments, the present invention is directed to a
method for treating a luteal phase defect in a patient in need
thereof, the method comprising administering to a patient a
monolithic intravaginal ring comprising (a) about 20% progesterone,
(b) about 75% MED-4840, and (c) about 5% mineral oil, wherein the
progesterone is homogeneously dispersed in the elastomer, wherein
the progesterone is released from the intravaginal ring at about 15
mg/day to about 25 mg/day in vivo, and wherein the intravaginal
ring is replaced after about every 7 days following administration
to the patient.
[0112] The following examples are for the purpose of illustration
of the invention only and are not intended in any way to limit the
scope of the present invention. It will thus be readily apparent to
one skilled in the art that varying substitutions and modifications
may be made to the invention disclosed herein without departing
from the scope and spirit of the invention.
EXAMPLES
Example 1
[0113] FIG. 2 depicts a process flow chart representing a process
for preparing a monolithic intravaginal ring of the present
invention. Micronized progesterone, MED-4840 elastomer part A, and
mineral oil were combined to form a homogeneous mixture ("the part
A mix"). Micronized progesterone, MED-4840 elastomer part B, and
mineral oil were combined to form a second homogeneous mixture
("the part B mix").
[0114] The part A mix was prepared by placing about 20% (by weight
of the final product) micronized progesterone, about 75% (by weight
of the final product) MED-4840 part A polysiloxane, and about 5%
(by weight of the final product) mineral oil in a Ross DPM-4 mixer
(Ross double planetary mixer and dispenser supplied by Charles Ross
& Son, Hauppauge, N.Y.), where the ingredients were mixed and
degassed under vacuum for about 30 minutes. The part A mix was then
transferred to pre-weighed disposable cartridges.
[0115] The part B mix was prepared by placing about 20% (by weight
of the final product) micronized progesterone, about 75% (by weight
of the final product) MED-4840 part B polysiloxane and about 5% (by
weight of the final product) mineral oil in a Ross DPM-4 mixer,
where the ingredients were mixed and degassed under vacuum for
about 30 minutes. The part B mix was then transferred to
pre-weighed disposable cartridges.
[0116] The part A mix and the part B mix cartridges were then
placed on separate pumps of a Gluco P20LS injection molding machine
(supplied by Gluco, Jenison, Mich.). The machine then injected both
the A and B mixes at a 1:1 ratio into a static mixer to produce a
homogeneous mix in-line. The in-line homogeneous mix was
immediately injected into a multi-cavity mold for filling at
ambient temperature.
[0117] The filled molds were removed from the machine and
transferred to a Grieve oven (Grieve Corp., Round Lake, Ill.) for
curing at about 90.degree. C. for about eight hours. The molds were
then allowed to cool to room temperature and disassembled to remove
the rings. Entry and exit runners and flashing were removed from
the rings, which were then trimmed prior to packaging in
heat-sealed foil pouches.
[0118] The process yielded a monolithic intravaginal ring with a
composition as listed in Table 1, with an outside diameter of about
55 mm, an inside diameter of about 38 mm, and a cross-sectional
diameter of about 8.5 mm (as depicted in FIG. 1).
[0119] The in vitro dissolution profile of the intravaginal ring
was determined using an Orbital shaker containing 250 mL of 0.008 M
SDS at 37.degree. C. at 50 rpm. These results are listed in FIG. 5.
When administered to the vaginal tract of a patient, the
intravaginal ring releases about 10 mg/day to about 30 mg/day of
progesterone over about 7 days.
TABLE-US-00001 TABLE 1 Composition of the monolithic intravaginal
ring of Example 1 (mass/g) (% wt of ring) Micronized Progesterone
1.8 20 Mineral Oil 0.45 5 MED-4840 Part A 3.375 37.5 MED-4840 Part
B 3.375 37.5 Total 9.000 100
Example 2
[0120] A pharmacodynamic study to compare an intravaginal ring of
Example 1 to a progesterone vaginal gel for luteal phase
replacement was conducted.
[0121] This was a single-center, open-label, randomized,
active-controlled, comparative, pharmacodynamic study to evaluate a
single dose of progesterone, delivered by vaginal ring, for
resultant endometrial transformation and luteal phase replacement.
The study had 2 treatment arms. One investigator enrolled and
randomized 20 eligible women aged 18-50, with 10 women per
treatment arm (21 subjects were randomized and one subject
discontinued from the vaginal gel treatment arm when she was found
to have cervical dysplasia on her Pap smear). The overall study
duration for each patient was approximately 11/2 months. The
subject demographics are shown in Table 2.
TABLE-US-00002 TABLE 2 Subject Demographics Mock Cycle ET Cycle
Progesterone Progesterone Progesterone Progesterone Vaginal Ring
Vaginal Gel Vaginal Ring Vaginal Gel N = 10 N = 11 N = 5 N = 4
Race: African- 2 (20.0%) 3 (27.3%) 1 (20.0%) 0 (0.0%) American
Caucasian 8 (80.0%) 8 (72.7%) 4 (80.0%) 4 (100%) Age (yrs): Mean
(SD) 41.0 (5.42) 39.1 (6.12) 43.0 (3.39) 39.8 (7.23) Min/Max
30.0/47.0 30.0/49.0 38.0/47.0 33.0/50.0 Body Mass Index
(kg/m.sup.2): Mean (SD) 27.7 (4.84) 27.5 (6.73) 25.4 (2.0) 25.2
(3.63) Min/Max 21.7/36.9 19.6/40.5 23.2/27.5 20.2/28.4
[0122] All patients met all inclusion and none of the exclusion
criteria as specified in the protocol. Continued participation in
the study depended on the patient meeting the protocol requirement
at the randomization visit. The study duration was 31 days plus two
weeks of post-treatment follow-up. In the first 14 days, estradiol
pre-treatment was given in attempt to generate a proliferative
phase of the endometrium.
[0123] Subjects enrolled in the mock cycle received oral
contraceptive pills ("OCPs") for 2 weeks and a GnRH agonist
(Lupron.RTM., TAP Pharmaceuticals, Chicago, Ill.) to suppress
ovarian function. The GnRH agonist was initiated on day 8 of the
OCPs in the cycle preceding the mock and/or transfer cycle and
continued until estradiol patches were initiated. The estradiol
regimen was determined by the site's mock cycle protocol and/or the
clinical investigator's discretion. Estradiol pre-treatment was
generally administered in a step-up fashion (0.2 mg days 1-7, 0.3
mg days 8-11 and 0.4 mg days 12-14 every other day, Vivelle
patches) to generate a proliferative phase of the endometrium.
[0124] Subjects with an endometrial thickness >6 mm were
randomized in a 1:1 fashion to either a progesterone intravaginal
ring (10-30 mg/day, Duramed Research, Inc., Bala Cynwyd, PA) or a
progesterone vaginal gel (Crinone.RTM., 180 mg/day, Columbia
Laboratories, Inc., Livingston, N.J.) and taught to administer the
product. A progesterone intravaginal ring 10-30 mg/day (in vitro
release rate) or progesterone vaginal gel (180 mg/day), together
with estradiol (per the site's protocol, e.g., 0.2 mg/day), was
administered over the next 18 days to transform the endometrium to
the secretory phase. The progesterone intravaginal ring was
replaced one time on day 8, while the vaginal gel was administered
twice a day for the full 18 days of progesterone dosing. Serum
progesterone and estradiol samples were collected at cycle day 0,
14, 15, 16, 18, 21, 22, 23, 25, 28, and 31. An endometrial biopsy
was performed on cycle day 25 or 26 and endometrial dating was
performed according to Noyes et al., Fertil. Steril., 1:3-25
(1950). Intravaginal ring compliance was determined at each study
visit. Vaginal colposcopy was performed at screening and on cycle
day 31 to determine whether there was potential vaginal and
cervical irritation.
[0125] The objectives of the study were to determine in women with
clinical or medically-induced agonadism (who were administered the
intravaginal ring) (a) the proportion of patients with adequate
endometrial transformation (on endometrial biopsy) as determined by
histological dating of the endometrium, (b) progesterone and
estradiol levels in the serum obtained from patients, and (c) the
safety and tolerability of progesterone delivered by an
intravaginal ring as compared with a progesterone vaginal gel. The
study was performed on twenty patients with an estrogen-primed
endometrium.
[0126] Subjects were women aged 18-50 with clinical or
medically-induced agonadism who were eligible for oocyte donation.
Subjects with a history of more than two failed donor egg cycles,
significant prior uterine surgery, hysterectomy, or clinically
significant uterine pathology were excluded from the study.
[0127] The intravaginal ring of Example 1 was administered to the
subject, and the duration of the dosing regimen lasted 18 days,
wherein the intravaginal ring was replaced once in the 18 day
period, on day 8. In subjects that were administered the
progesterone vaginal gel, the vaginal application of 180 mg/day for
18 days was dosed at 90 mg twice a day.
[0128] The primary efficacy measure was the presence or absence of
adequate secretory transformation of the endometrium as determined
by biopsy on either cycle day 25 or 26. The proportion of patients
having an in-phase biopsy and adequate endometrial secretory
transformation determined by histological dating of the
endometrium, as defined by the histological test results, was
calculated. The intravaginal ring of Example 1 adequately
transformed the endometrium to secretory phase in 8 out of 10
patients while the vaginal gel 180 mg/day did so in 10 out of 10
patients.
[0129] However, additional outside factors may have contributed to
the failure in the two patients who did not exhibit endometrial
transformation. One subject had a non-datable endometrium;
predominantly inactive with tubal metaplasia, but showing small
foci of secretory exhaustion, suggestive of an uneven end-organ
response to the hormonal milieu (i.e., irregular ripening). There
was a fibroid found in surgery post-study, which could have
affected blood supply to the endometrium. Post-surgery, the subject
went through a mock cycle with micronized progesterone 200 mg
t.i.d. and underwent a biopsy that showed adequate transformation.
This same subject underwent a donor egg 1VF using micronized
progesterone that resulted in a negative .beta.hCG. The subject is
considering one more IVF attempt with a donor egg. The second
subject was a 37 year-old with gonadal dysgenesis (streak ovaries
and ovarian failure) and no periods since birth who exhibited a
mixed inactive and exhausted secretory endometrium; features
favored late secretory phase, but no precise dating was possible.
This subject was screened twice for the study, and after the first
estradiol pre-treatment had an endometrial lining <6 mm. The
subject was allowed to re-screen for the study; and after the
second screening and estradiol pre-treatment, the subject had an
endometrial lining >6 mm. Post-study, the subject went through a
mock cycle with IM progesterone, and underwent a biopsy that showed
adequate transformation. This same subject underwent a donor egg
IVF using IM progesterone (50 mg) that resulted in a positive
.beta.hCG and an ongoing pregnancy with delivery.
[0130] Estradiol serum levels in the intravaginal ring treatment
group were comparable with that of the Crinone.RTM. group, while
progesterone serum levels in the intravaginal ring treatment group
were on average lower than those for Crinone.RTM. (6.02 ng/mL vs.
14.18 ng/mL). Estradiol serum levels of the treatment groups at
various time points is shown below in Table 3 and schematically in
FIG. 3. Progesterone serum levels of the treatment groups at
various time points is shown below in Table 4 and schematically in
FIG. 4.
TABLE-US-00003 TABLE 3 Estradiol Serum Levels and Changes During
the Study Estradiol Progesterone Vaginal Ring 8% Progesterone
Vaginal Gel (ng/mL) N Mean(Std) Median (Min, Max) N Mean(Std)
Beginning 10 19.8 (16.29) 10.0 (10.0, 61.0) 10 32.4 (44.61) Cycle
Day 14 10 280.4 (91.69) 264.0 (172.0, 410.0) 10 345.1 (100.85)
Change from 10 260.6 (86.82) 242.5 (162.0, 394.0) 10 312.7 (121.15)
Beginning to Day 14 10 229.0 (145.69) 205.0 (108.0, 616.0) 10 283.0
(111.48) Cycle Day 15 Change from 10 209.2 (148.51) 180.0 (98.0,
606.0) 10 250.6 (118.12) Beginning to Day 15 10 188.2 (93.35) 160.5
(61.6, 346.0) 10 229.9 (102.28) Cycle Day 16 Change from 10 168.4
(87.00) 150.5 (50.0, 293.0) 10 197.5 (112.30) Beginning to Day 16
10 198.2 (74.44) 199.5 (84.1, 322.0) 10 232.9 (145.87) Cycle Day 18
Change from 10 178.4 (71.55) 172.0 (61.1, 296.0) 10 200.5 (159.59)
Beginning to Day 18 10 216.5 (139.59) 167.5 (64.8, 496.0) 10 186.6
(82.09) Cycle Day 21 Change from 10 196.7 (142.31) 143.0 (41.8,
486.0) 10 154.2 (96.53) Beginning to Day 21 10 221.0 (126.25) 184.0
(76.5, 504.0) 10 259.1 (86.13) Cycle Day 22 Change from 10 201.2
(119.09) 174.0 (53.5, 478.0) 10 226.7 (95.57) Beginning to Day 22
10 236.8 (146.75) 157.5 (92.0, 514.0) 10 212.7 (79.13) Cycle Day 23
Change from 10 217.0 (144.87) 141.0 (64.0, 504.0) 10 180.3 (75.48)
Beginning to Day 23 10 190.5 (81.33) 169.0 (100.0, 355.0) 10 193.1
(145.48) Cycle Day 25 Change from 10 170.7 (77.35) 156.5 (90.0,
329.0) 10 160.7 (123.48) Beginning to Day 25 10 223.7 (104.99)
184.0 (102.0, 418.0) 10 282.1 (158.28) Cycle Day 28 Change from 10
203.9 (98.75) 174.0 (79.0, 392.0) 10 249.7 (153.35) Beginning to
Day 28 10 124.2 (73.10) 123.0 (34.0, 296.0) 10 115.3 (63.02) Cycle
Day 31 Change from 10 104.4 (69.67) 96.0 (24.0, 270.0) 10 82.9
(54.81) Beginning to Day 31 Estradiol 8% Progesterone Vaginal Gel
Total (ng/mL) Median (Min, Max) N Mean(Std) Median (Min, Max)
Beginning 10.0 (10.0, 152.0) 20 26.1 (33.32) 10.0 (10.0, 152.0)
Cycle Day 14 339.0 (232.0, 498.0) 20 312.8 (99.50) 304.0 (172.0,
498.0) Change from 318.5 (110.0, 488.0) 20 286.7 (106.01) 277.5
(110.0, 488.0) Beginning to Day 14 274.5 (141.0, 453.0) 20 256.0
(129.26) 208.5 (108.0, 616.0) Cycle Day 15 Change from 201.5
(112.0, 443.0) 20 229.9 (132.31) 181.5 (98.0, 606.0) Beginning to
Day 15 207.5 (65.9, 408.0) 20 209.0 (97.68) 192.0 (61.6, 408.0)
Cycle Day 16 Change from 188.0 (25.0, 398.0) 20 182.9 (98.91) 169.0
(25.0, 398.0) Beginning to Day 16 186.5 (102.0, 501.0) 20 215.6
(114.11) 198.0 (84.1, 501.0) Cycle Day 18 Change from 176.5 (-50.0,
491.0) 20 189.5 (120.90) 172.0 (-50.0, 491.0) Beginning to Day 18
172.5 (66.0, 351.0) 20 201.5 (112.50) 167.5 (64.8, 496.0) Cycle Day
21 Change from 152.5 (13.0, 341.0) 20 175.4 (120.34) 152.5 (13.0,
486.0) Beginning to Day 21 226.0 (187.0, 436.0) 20 240.0 (106.99)
201.5 (76.5, 504.0) Cycle Day 22 Change from 201.0 (74.0, 380.0) 20
213.9 (105.90) 183.0 (53.5, 478.0) Beginning to Day 22 191.5
(135.0, 382.0) 20 224.8 (115.41) 172.5 (92.0, 514.0) Cycle Day 23
Change from 156.5 (106.0, 372.0) 20 198.7 (113.99) 151.5 (64.0,
504.0) Beginning to Day 23 142.5 (63.8, 539.0) 20 191.8 (114.72)
154.5 (63.8, 539.0) Cycle Day 25 Change from 123.0 (53.8, 483.0) 20
165.7 (100.41) 135.0 (53.8, 483.0) Beginning to Day 25 309.0 (88.9,
610.0) 20 252.9 (134.11) 212.0 (88.9, 610.0) Cycle Day 28 Change
from 247.0 (78.9, 600.0) 20 226.8 (127.72) 192.5 (78.9, 600.0)
Beginning to Day 28 96.0 (47.0, 234.0) 20 119.7 (66.58) 112.5
(34.0, 296.0) Cycle Day 31 Change from 71.5 (17.0, 178.0) 20 93.6
(62.00) 79.5 (17.0, 270.0) Beginning to Day 31
TABLE-US-00004 TABLE 4 Progesterone Serum Levels and Changes During
the Study Progesterone Progesterone Vaginal Ring 8% Progesterone
Vaginal Gel Total (ng/mL) N Mean(Std) Median (Min, Max) N Mean(Std)
Median (Min, Max) N Mean(Std) Median (Min, Max) Beginning 10 0.9
(0.71) 0.6 (0.2, 2.5) 10 0.9 (0.32) 0.9 (0.6, 1.6) 20 0.9 (0.53)
0.8 (0.2, 2.5) Cycle Day 14 10 0.7 (0.33) 0.7 (0.1, 1.4) 10 0.8
(0.24) 0.8 (0.5, 1.2) 20 0.7 (0.28) 0.7 (0.1, 1.4) Change from 10
-0.2 (0.54) -0.1 (-1.5, 0.5) 10 -0.1 (0.21) -0.2 (-0.6, 0.2) 20
-0.2 (0.40) -0.1 (-1.5, 0.5) Beginning to Day 14 10 5.2 (2.00) 4.7
(3.3, 9.0) 10 11.9 (6.48) 11.6 (3.6, 26.0) 20 8.5 (5.79) 6.6 (3.3,
26.0) Cycle Day 15 Change from 10 4.3 (1.77) 3.4 (2.7, 7.3) 10 10.9
(6.46) 10.5 (2.6, 25.2) 20 7.6 (5.75) 5.8 (2.6, 25.2) Beginning to
Day 15 10 5.6 (1.85) 5.6 (3.5, 9.2) 10 13.3 (3.95) 14.0 (5.8, 19.7)
20 9.4 (4.96) 8.5 (3.5, 19.7) Cycle Day 16 Change from 10 4.7
(1.73) 4.5 (3.0, 8.5) 10 12.4 (3.89) 12.6 (5.2, 18.9) 20 8.5 (4.92)
7.3 (3.0, 18.9) Beginning to Day 16 10 6.7 (1.96) 7.1 (4.0, 9.5) 10
13.0 (4.76) 12.8 (6.9, 23.4) 20 9.8 (4.80) 8.7 (4.0, 23.4) Cycle
Day 18 Change from 10 5.8 (1.90) 5.7 (3.4, 8.9) 10 12.0 (4.79) 11.9
(6.3, 22.6) 20 8.9 (4.80) 7.7 (3.4, 22.6) Beginning to Day 18 10
6.6 (1.70) 5.9 (4.6, 9.4) 10 13.2 (4.81) 12.2 (7.4, 22.4) 20 9.9
(4.89) 8.7 (4.6, 22.4) Cycle Day 21 Change from 10 5.7 (1.80) 5.2
(3.2, 8.8) 10 12.3 (4.77) 11.3 (6.8, 21.6) 20 9.0 (4.89) 7.7 (3.2,
21.6) Beginning to Day 21 10 6.5 (2.00) 6.2 (3.9, 9.7) 10 14.8
(6.02) 15.8 (6.6, 26.3) 20 10.6 (6.11) 8.7 (3.9, 26.3) Cycle Day 22
Change from 10 5.5 (2.01) 5.0 (3.4, 8.5) 10 13.9 (6.00) 14.5 (6.0,
25.5) 20 9.7 (6.10) 7.9 (3.4, 25.5) Beginning to Day 22 10 6.5
(1.80) 6.5 (3.5, 9.3) 10 16.9 (10.31) 14.5 (7.2, 38.5) 20 11.7
(8.98) 7.9 (3.5, 38.5) Cycle Day 23 Change from 10 5.6 (1.92) 5.3
(3.0, 8.7) 10 16.0 (10.33) 13.5 (5.9, 37.7) 20 10.8 (9.00) 7.2
(3.0, 37.7) Beginning to Day 23 10 5.7 (1.54) 5.8 (3.7, 7.8) 10
14.7 (6.37) 16.2 (5.4, 26.8) 20 10.2 (6.46) 7.1 (3.7, 26.8) Cycle
Day 25 Change from 10 4.8 (1.48) 4.7 (3.1, 7.4) 10 13.8 (6.42) 15.2
(4.8, 26.0) 20 9.3 (6.47) 6.1 (3.1, 26.0) Beginning to Day 25 Cycle
Day 28 10 5.7 (1.38) 6.0 (3.8, 8.0) 10 15.1 (7.19) 15.7 (6.2, 29.0)
20 10.4 ( 6.96) 6.9 (3.8, 29.0) Change from 10 4.8 (1.46) 4.7 (3.2,
7.8) 10 14.2 (7.07) 15.0 (5.5, 27.7) 20 9.5 (6.91) 5.9 (3.2, 27.7)
Beginning to Day 28 Cycle Day 31 10 5.7 (1.52) 5.5 (3.2, 8.1) 10
14.7 (6.54) 14.4 (3.7, 27.3) 20 10.2 (6.51) 7.7 (3.2, 27.3) Change
from 10 4.8 (1.52) 4.7 (2.6, 7.7) 10 13.7 (6.57) 13.8 (3.1, 26.5)
20 9.3 (6.52) 6.6 (2.6, 26.5) Beginning to Day 31
[0131] Also in this study the intravaginal ring was observed to be
as safe as the vaginal gel, except for the observation that most
patients in the intravaginal ring treatment group had mild vaginal
bleeding/spotting near the end of the treatment. A summary of
breakthrough bleeding/spotting for the treatment groups and in
individual subjects is shown in Tables 5 and 6, respectively.
TABLE-US-00005 TABLE 5 Vaginal Bleeding/Spotting During Study for
the Treatment Groups 8% Progesterone Progesterone Vaginal Ring
Vaginal Gel Total Visit (N = 10) (N = 11) (N = 21) Total Bleeding/
9 (90.00) 5 (45.45) 14 (66.67) Spotting Patients Cycle Day 25 5
(50.00) 4 (36.36) 9 (42.86) Cycle Day 26 4 (40.00) 3 (27.27) 7
(33.33) Cycle Day 27 4 (40.00) 1 (9.09) 5 (23.81) Cycle Day 28 6
(60.00) 0 (0.00) 6 (28.57) Cycle Day 29 8 (80.00) 0 (0.00) 8
(38.10) Cycle Day 30 9 (90.00) 0 (0.00) 9 (42.86) Cycle Day 31 7
(70.00) 0 (0.00) 7 (33.33)
TABLE-US-00006 TABLE 6 Summary of Breakthrough Vaginal
Bleeding/Spotting in Individual Subjects Vaginal Endometrial Biopsy
Results Vaginal bleeding Vaginal bleeding Cycle Day by after
biopsy, but bleeding Patient Study before Histologic before Visit 9
on/after Visit 9 # Drug biopsy? Phase Dating (Cycle Day 28)? (Cycle
Day 28)? AEs reported 0103 VR Secretory 23 Metrorrhagia,
Onychomycosis 0105 VR Inactive N/A Metrorrhagia, Myalgia 0107 VR
Secretory 23 light spotting light spotting Metrorrhagia, Limb
Discomfort 0109 VR Secretory 24 light spotting light spotting
Metrorrhagia, Dysmenorrhoea 0113 VR Secretory 23 Metrorrhagia 0114
VR Secretory 25 light spotting Metrorrhagia, Nasopharyngitis 0123
VR Cycle Day Mixed Pattern N/A Vaginal Discharge, 21, Upper
Respiratory Scant Tract Infection amount of (URTI), Skin pink
Irritation tinged mucous on VR 0124 VR Secretory 25** light
spotting Metrorrhagia 0127 VR Secretory 23 red/brown spotting
Metrorrhagia, Nausea 0129 VR Secretory 25 Spotting Metrorrhagia,
URTI, Ear Pain, Breast Discomfort, Post Procedural Complication
0102 Gel Secretory 25 moderate to heavy N/A 0106 Gel Secretory 23
light spotting Pelvic Pain, Sinus Headaches, Pharyngolaryngeal Pain
0108 Gel Secretory 23 Nausea 0111 Gel Prior to Secretory 24 light
spotting Headaches, URTI Visit 1, moderate to heavy 0115 Gel
Secretory 25 URTI, Uterine Cervical Erosion, Vaginal Erosion 0122
Gel Prior to Secretory 24 light spotting Metrorrhagia, Visit 0 -
Headache, during Withdrawal Bleed, estradiol Dysmenorrhoea pre-
treatment (moderate) 0125 Gel Secretory 25 Vulvovaginal Discomfort
Abdominal Pain, Post Procedural Complication 0126 Gel Secretory 25
one spec dry blood Breast Discomfort, Cervical Polyp, Abdominal
Pain 0128 Gel Secretory 24 light spotting Abdominal Pain, Post
Procedural Complication 0130 Gel Secretory 24 Abdominal Pain Lower
*vaginal bleeding after biopsy cases were reported by the site via
email or phone; vaginal bleeding after biopsy was not considered an
AE, as it is an expected result of the procedure; therefore, the
above information was not captured on the CRFs, nor entered into
the database **patchy decidualization of stroma giving a range of
appearances from POD 8 to POD 11
[0132] Subjects with adequate secretory endometrial transformation
in the mock cycle who had accepted an oocyte donor and were
synchronized with this donor were invited to participate in a
follow-on embryo transfer cycle. Subjects were kept on the same
progesterone treatment to which they had been randomized in the
mock cycle. For subjects in the intravaginal ring group, a new
intravaginal ring was placed at the time of transfer, and the
intravaginal ring was scheduled to be replaced weekly until the
pregnancy test was performed 2 weeks after embryo transfer.
Subjects in the vaginal gel group continued to self-administer the
vaginal gel twice daily until 2 weeks after embryo transfer. If a
pregnancy was detected, the estradiol replacement was continued for
a total of 8 weeks and the progesterone for a total of 10 weeks
after embryo transfer. Pelvic ultrasound was performed at 8 weeks
and 12 weeks to confirm a clinical pregnancy. Follow-up of any
pregnancies continued until delivery.
[0133] Biochemical pregnancy, clinical pregnancy (8 and 12 weeks of
pregnancy), and live birth rates were assessed. A biochemical
pregnancy was defined as a transient increase in hCG levels,
followed by a decrease. A clinical pregnancy was defined by the
visualization of a gestational sac with fetal heart motion on
ultrasound. The primary efficacy measure in the embryo transfer
cycle was the clinical pregnancy rate at 8 weeks of pregnancy,
where the gestational age (duration of pregnancy) in weeks was
defined as commencing 2 weeks prior to embryo transfer, which would
correlate in a normally ovulating and cycling woman with the first
day of her last menstrual period. Secondary outcome measures in the
embryo transfer cycle included clinical pregnancy rates at 12 weeks
of pregnancy and live birth rates.
[0134] A total of 11 subjects consented, with 9 subjects undergoing
an embryo transfer. There were a total of 5 transfers in the
intravaginal ring treatment group and 4 in the vaginal gel
treatment group. Of these transfers, 4 of 5 (80%) intravaginal ring
subjects and 1 of 4 (25%) vaginal gel subjects became pregnant
(confirmed 2 weeks after embryo transfer) resulting in 4 term
singleton deliveries and one set of twins delivering at 34 weeks.
The full results of the pregnancies and live births are outlined in
Table 7. Individual subject data is shown in Table 8. There were no
biochemical pregnancies and no miscarriages in the pregnant
subjects. One of the pregnant intravaginal ring subjects was
discontinued from the study and switched to intramuscular
progesterone due to the bleeding pattern at 9 weeks of pregnancy (7
weeks after embryo transfer).
TABLE-US-00007 TABLE 7 Biochemical Pregnancy, Clinical Pregnancy,
and Live Birth Rates Progesterone Progesterone All Vaginal Ring
Vaginal gel subjects Number of fresh transfers 5 4 9 Number of
embryos transferred 2 2 2 Biochemical pregnancy [N (%)] 0 (0) 0 (0)
0 (0) Miscarriages [N (%)] 0 (0) 0 (0) 0 (0) 8 week clinical
pregnancy [N 4 (80) 1 (25) 5 (56) (%)] 12 week clinical pregnancy
[N 3* (60) 1 (25) 4* (44) (%)] Livebirth [N (%)] 3* (60) 1 (25) 4*
(44) *One subject who became pregnant on the progesterone VR was
discontinued from the study at Week 9 of pregnancy due to vaginal
bleeding. This subject was switched to IM progesterone and
sustained the pregnancy until a live birth.
TABLE-US-00008 TABLE 8 Individual Subject Data Vaginal Cramping
Vaginal bleeding Patient Study During spotting during No. Drug
Pregnancy? Study? during study? study? AEs reported 0103 VR Yes ET
+ 24 days ET + 24 days ET + 46 days Nausea-intermittent;
vomiting-intermittent; pelvic [switched to ET + 43 days ET + 25
days cramping; vaginal spotting; vaginal bleeding; IM progesterone
ET + 44 days ET + 26 days lower quadrant abdominal cramping due to
vaginal bleeding; withdrawn from study; live birth] 0107 VR No
Light-headed; sore throat 0109 VR Yes (twins) ET + 9 days ET + 28
days Vulvovaginal candidiasis; vaginal spotting (reports [Completed
ET + 20 days ET + 29 days progressively increased spotting toward
time of vaginal ring study] ET + 21 days change; cessation of
spotting when new ring is inserted); ET + 23-28 days gestational
diabetes; mild hypertension; indigestion- ET + 30-41 days
intermittent ET + 43-49 days 0113 VR Yes (twins)
Nausea-intermittent; indigestion-intermittent; diarrhea- [Completed
intermittent study; no reported spotting/bleeding] 0114 . VR Yes ET
+ 34 days ET + 34 days Vaginal Spotting; headache-intermittent;
insomnia; pelvic ET + 38 days cramps-intermittent; upper
respiratory infection ET + 40-47 days 0102 Gel No Upper respiratory
infection 0106 Gel No - discontinued Sore throat prior to embryo
transfer 0115 Gel No ET + 2-9 Indigestion; cold sore - oral; pelvic
cramping; pelvic days pressure; seasonal allergies; headache 0122
Gel No ET + 5-11 Headache, intermittent; lower abdominal cramping,
days intermittent; upper respiratory infection 0125 Gel Yes ET + 41
days Intermittent nausea; left arm axilla, swollen glands; left
[Completed axilla tenderness; left axilla, swollen glands; lower
study] abdominal cramping; upper respiratory infection; vaginal
spotting
[0135] The treatment emergent adverse events reported were similar
among the two treatment groups, with a few exceptions. More adverse
vaginal/cervical findings and abdominal pain were reported in the
vaginal gel group, and more vaginal bleeding/spotting was reported
in the vaginal ring treatment group. A summary of adverse events is
presented in Table 9.
TABLE-US-00009 TABLE 9 Adverse Events Occurring in >1 Subject
Mock Cycle Vaginal Ring Vaginal Gel N = 10 N = 11 Any Adverse Event
10 9 Metrorrhagia 9 0 Dysmenorrhea 1 1 Cervix erythema 1 1
Post-procedural 1 2 complication Abdominal pain 0 3 Embryo Transfer
Cycle Vaginal Ring Vaginal Gel N = 5 N = 4 Any Adverse Event 5 3
Dyspepsia 2 1 Nausea 2 1 Lower abdominal pain 1 2 Metrorrhagia 3 1
Pelvic pain 2 1 Upper respiratory 1 2 infection Headache 1 2
[0136] There were four subjects with adverse vaginal and/or
cervical findings in the mock cycle; 3 in the vaginal gel group and
1 in the intravaginal ring group. The reported vaginal/cervical
adverse events for the vaginal gel subjects included cervical face
ulceration, erythema, external vaginal irritation, grossly white
findings, petechiae, uterine cervical erosion, and vaginal erosion
with superficial peeling. The single VR patient with
vaginal/cervical findings was reported to have erythema.
[0137] During the mock cycle, there was expected vaginal
bleeding/spotting in both treatment groups on the day of, and up to
2 days after, the endometrial biopsy (cycle days 25-27). No
subjects in the vaginal gel group reported any vaginal
bleeding/spotting from cycle days 28-31, while 9 out of 10 subjects
did so in the intravaginal ring group (predominantly spotting).
None of the subjects in the intravaginal ring group were
discontinued due to bleeding/spotting during the mock cycle.
Bleeding/spotting in the intravaginal ring group occurred primarily
when an intravaginal ring was used for longer than 7 days. The
intravaginal ring was designed as a 7-day ring, and the second
intravaginal ring was left in place for 10 days in this study to
evaluate the impact of extending ring use beyond 7 days in case the
ring was inadvertently left in place for longer periods of time.
The vaginal spotting for the intravaginal ring group occurred
either on the day or day after the intravaginal ring would normally
be changed (on or after cycle day 28).
[0138] Within the intravaginal ring treatment group, there were no
reports of irritation, discomfort, or issues with intercourse due
to the intravaginal ring. In addition, there were no
discontinuations due to the ring falling out. There were no serious
adverse events, discontinuations due to a treatment-related adverse
event, or reports of vaginal hemorrhage during the study.
[0139] In the embryo transfer cycle, none of the subjects had
vaginal bleeding or spotting prior to the pregnancy test. Of the 5
subjects who achieved a pregnancy, 4 were using the intravaginal
ring and 1 used the vaginal gel. Three of 4 had some vaginal
bleeding or spotting during the pregnancy in the intravaginal ring
treatment group, commencing on embryo transfer day 24-34 or at 6-7
weeks gestation. The spotting/bleeding started at the point in the
pregnancy when serum progesterone levels were increasing due to
production by the trophoblasts. One of the 4 pregnant intravaginal
ring treatment subjects was switched to intramuscular progesterone
due to an irregular bleeding pattern at 7 weeks (after embryo
transfer). Two remaining women had mild spotting at 6-7 weeks which
did not require any treatment. Vaginal gel subjects had no vaginal
bleeding or spotting before or after pregnancy tests during the
treatment period. Of note, the twin pregnancy occurred in the
intravaginal ring group and this subject experienced no spotting
during the pregnancy.
Example 3
[0140] The intravaginal ring of Example 1 can be used in a study to
compare the efficacy of the intravaginal ring to a progesterone
vaginal gel for luteal phase supplementation for in vitro
fertilization. This study will be in women undergoing in vitro
fertilization with fresh eggs. Multiple sites will randomize
approximately 1300 eligible women in a 1:1 ratio to either a
progesterone intravaginal ring or a progesterone vaginal gel once
daily. Detailed past obstetrical history will be recorded,
including gravidity, parity, previous abortions, and ectopic
pregnancies.
[0141] The ovarian suppression/stimulation protocols will be a
Lupron.RTM. (leuprolide acetate) down-regulation protocol with a
combination of FSH (follicle stimulating hormone) and an
LH-containing product for stimulation (luteinizing hormone).
Suppression will take place during the cycle before the embryo
transfer cycle. After suppression, stimulation will begin once
down-regulation is achieved. The length of stimulation will be
dependent upon each patient, the site's standard protocols, and/or
the investigator's discretion. During stimulation, the patient will
be monitored to determine when to trigger ovulation for the patient
with hCG (Human Chorionic Gonadotropin). Egg retrieval will occur
approximately 35-37 hours after hCG administration and embryo
transfer will occur 3 or 5 days after egg retrieval. A serum
pregnancy test will be conducted 2 weeks after the egg retrieval.
Those patients with a .beta.hCG <5 mIU will be discontinued from
the study. Those patients with a .beta.hCG >5 mIU will continue
dosing with progesterone through 12 weeks of pregnancy, with an
evaluation of clinical pregnancy rates at 8 and 12 weeks of
pregnancy. All pregnancies will be followed until completion to
determine live birth rates. The overall study duration will be
approximately 10 months for patients who become pregnant and give
birth.
[0142] In each case the patients will be administered either a
progesterone intravaginal ring of Example 1 or the progesterone
vaginal gel. In each case the progesterone treatment will begin the
day after egg retrieval and continue through week 12 of pregnancy
(10 weeks post egg retrieval).
[0143] One half of the registered participants will be administered
the intravaginal ring of Example 1, which will be changed on a
weekly schedule, whereby the intravaginal ring will deliver between
about 10 mg of progesterone to about 30 mg of progesterone (in vivo
release) to the patient each day for about seven days. Similarly,
for the patients administered progesterone vaginal gel, treatment
will begin the day after egg retrieval and continue through week 12
of pregnancy (10 weeks post egg retrieval).
[0144] The co-primary objectives in this study are clinical
pregnancy rate (i.e., visualization of a gestational sac with fetal
heart motion present on ultrasound) at 8 weeks of pregnancy (6
weeks after egg retrieval) and at 12 weeks of pregnancy (10 weeks
after egg retrieval) using the intravaginal ring of Example 1 or
progesterone vaginal gel to provide progesterone supplementation.
In this study, pregnancy is defined as beginning 2 weeks prior to
egg retrieval. Secondary objectives include a study of live birth
rate, cycle cancellation rate, rate of spontaneous abortion, rate
of biochemical pregnancy, rate of ectopic pregnancy, and the safety
and tolerability of the intravaginal ring of Example 1.
CONCLUSION
[0145] All of the various embodiments or options described herein
can be combined in any and all variations. While the invention has
been particularly shown and described with reference to some
embodiments thereof, it will be understood by those skilled in the
art that they have been presented by way of example only, and not
limitation, and various changes in form and details can be made
therein without departing from the spirit and scope of the
invention. Thus, the breadth and scope of the present invention
should not be limited by any of the above described exemplary
embodiments, but should be defined only in accordance with the
following claims and their equivalents.
[0146] All documents cited herein, including journal articles or
abstracts, published or corresponding U.S. or foreign patent
applications, issued or foreign patents, or any other documents,
are each entirely incorporated by reference herein, including all
data, tables, figures, and text presented in the cited
documents.
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